Method of treating skin diseases

ABSTRACT

Skin diseases with keratinization and allergic or inflammatory skin diseases are treated by orally or parenterally administering to an adult human patient from 40 mg to 4 g/day of a polyprenyl compound having the formula (I): ##STR1## in which each of n and m is 0, 1, or 2, n+m is 0, 1 or 2, A is ##STR2## and B is ##STR3## [in which R represents the hydroxyl group, a lower alkoxy group, or ##STR4## (wherein each of R 1  and R 2  is the hydrogen atom, a lower alkyl group or an aryl group)]; provided that R is a lower alkoxy or ##STR5## if n is 1, m is 0, a is ##STR6## and B is ##STR7##

This invention relates to an anti-cancer agent which comprises apolyprenyl compound having the formula (I): ##STR8## in which each of nand m is 0, 1 or 2, n+m is 0, 1 or 2, A is ##STR9## and B is ##STR10##in which R represents the hydroxyl group, a lower alkoxy group, or##STR11## (wherein each of R₁ and R₂ is a hydrogen atom, a lower alkylgroup or an aryl group); provided that R is lower alkoxy or ##STR12## ifn is 1, m is 0, A is ##STR13## and B is ##STR14##

Examples of the lower alkoxy groups represented by R in theabove-mentioned formula (I) include methoxy, ethoxy, i-propoxy,n-propoxy, t-butoxy and n-butoxy. Examples of the lower alkyl groupsrepresented by R₁ and R₂ include methyl, ethyl, i-propyl, n-propyl,t-butyl and n-butyl, and examples of the aryl groups represented by R₁and R₂ include phenyl and a phenyl group having substituent groups suchas hydroxyl, a lower alkyl group or halogen. If R in the formula (I) ishydroxyl, the compound may be in the form of a salt such as sodium orpotassium salt.

W. Bollag, et al. reported in Europ. J. Cancer, Vol. 10, p 731 (1974)that retinoides such as ethyl9-(2,3,6-trimethyl-4-methoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoatehave anti-cancer activity. These retinoide compounds, however, arehighly toxic, and further have problems such as causing hypervitaminosisof Vitamin A when administered.

The present invention provides an anti-cancer agent comprisingpolyprenyl compounds of the formula (I). The polyprenyl compounds of theformula (I) show remarkable anti-cancer activity and are highly safecompounds. For instance, these polyprenyl compounds do not causehypervitaminosis of Vitamin A. Further, toxicities of the polyprenylcompounds of the formula (I) other than hypervitaminosis are also at lowlevels.

Moreover, the polyprenyl compounds of the formula (I) are of value astherapeutic agents for treatment of skin diseases with keratinization ortreatment of allergic or inflammatory skin diseases, such as psoriasis,acne, acne vulgaris, Darier's disease, palmoplantar pustulosis, lichenplasnus, ichthyosis, erythroderma, pityriasis rubra pilasis, andkeratosis senilis, as well as the therapeutic agents for treatment ofcancer and precancerous conditions.

Some of the polyprenyl compounds of the formula (I) are already known.For instance, some polyprenyl compounds represented by the formula (I)are described in Japanese Patent Provisional Publication 54-5042, Helv.Chim. Acta., Vol. 35, p. 1649 (1952), Agr. Biol. Chem., Vol. 34, No. 8,p. 1184 (1970), and J. Chem. Soc., (C) p. 2154 (1966). However, thereare no description about the anti-cancer activity of these compounds inthese references.

Examples of the known polyprenyl compounds represented by the formula(I) include:

6,10,14-trimethyl-3,5,9,13-pentadecatetraene-2-one

6,10,14-trimethyl-3,5-pentadecadiene-2-one

6,10,14,18-tetramethyl-3,5,9,13,17-nonadecapentaene-2-one

6,10,14,18-tetramethyl-3,5,9,17-nonadecatetraene-2-one

6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-one

6,10,14,18-tetramethyl-3,5,-nonadecadiene-2-one

3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid ethyl3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoate

3,7,11-trimethyl-2,4,6,10-dodecatetraenoic acid

ethyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenoate

methyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate.

Examples of the novel polyprenyl compounds represented by the formula(I) include:

3,7,11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoic acid

3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoic acid

3,7,11,15-tetramethyl-2,4,6-hexadecatrienoic acid

3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecahexaenoic acid

3,7,11,15-tetramethyl-2,4,6,10-hexadecatetraenoic acid

3,7,11,15,19-pentamethyl-2,4,6,8,10,14,18-eicosaheptaenoic acid

3,7,11,15,19-pentamethyl-2,4,6,10,18-eicosapentaenoic acid

ethyl 3,7,11,15-tetramethyl-2,4,6-hexadecatrienoate

ethyl 3,7,11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoate

methyl 3,7,11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoate

ethyl 3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecahexaenoate

3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

N-(p-hydroxyphenyl)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

N-ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

N,N-dimethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

N-ethyl-3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecahexaenoamide

N-ethyl-3,7,11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoamide

ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate

propyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate

3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid

N,N-dimethyl-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoamide

N-ethyl-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoamide.

The novel polyprenyl compounds represented by the formula (I) such asexemplified as above can be prepared in the manner described in theaforementioned publications, in the process given hereinafter, or in theconventional manner.

The results of the pharmacological tests and toxicity tests on thepolyprenyl compounds of the formula (I) are set forth below.

Pharmacological Tests (Anti-cancer Activity) (1) Test procedure

A mouse (ICR strain, female, 60 days age) was shaved at the back of theneck (to the extent to 5 cm²). 7,12-Dimethylbenzo[2]-anthracene wasdissolved in acetone to give 75 mg./100 ml. solution. The so preparedsolution was applied to the mouse on the 60th aged day and further onthe 75th aged day in the amount of 0.2 ml. per mouse.

Crotonic oil was dissolved in acetone to give 250 mg./100 ml. solution,and the so prepared solution was applied to the mouse in the amount of0.2 ml. per mouse, twice a week until the treatment was started. When3-7 papillomata (diameter of 3-8 mm. for each, and total diameter of30-60 mm.) were produced for a mouse, the treatment was started.

The compound to be tested (test compound) was dissolved in groundnut oilto give 20 mg./ml. solution, and administered orally to the mouse. Thesolution was administered 10 times for 14 days (once a day), and thediameters of the papillomata were measured on the 14th day to determinethe total diameter for each mouse. Ratio of increase or decrease of thepapillomata was calculated from the total diameter on the 14th day andthe total diameter measured prior to the starting of administration ofthe test compound. This value was adopted for evaluating the anti-canceractivity.

(2) Results

                                      TABLE 1                                     __________________________________________________________________________                                                    Number                                                                              Ratio of                                                                of    increase or                                                             mice  decrease of             Test Compound                                   tested                                                                              papillomata             __________________________________________________________________________                                                          (%)                     Groundnut only (Control)                        3     +17.1                    ##STR15##                                      5     -24.0                    ##STR16##                                      4     -19.5                    ##STR17##                                      4     -10.2                    ##STR18##                                      5     -26.3                    ##STR19##                                      5     -25.5                    ##STR20##                                      17    -17.5                    ##STR21##                                      5     -12.7                    ##STR22##                                      7     -6.5                     ##STR23##                                      7     -8.2                    __________________________________________________________________________     Remarks: The compounds identified by the structural formulae in Table 1       correspond to the following polyprenyl compounds.                             (1) 3,7,11,15,19pentamethyl-2,4,5,10,14,18-eicosahexaenoic acid               (2) 3,7,11,15tetramethyl-2,4,6,14-hexadecatetraenoic acid                     (3) ethyl 3,7,11,15tetramethyl-2,4,6,14-hexadecatetraenoate                   (4) 3,7,11,15tetramethyl-2,4,6,8,10,14-hexadecahexaenoic acid                 (5) Nethyl 3,7,11,15tetramethyl-2,4,6,10,14-hexadecapentaeneamide             (6) ethyl 3,7,11,15tetramethyl-2,4,6,10,14-hexadecapentaenoate                (7) 6,10,14,18tetramethyl-3,5,9,13,17-nonadecapentaene-2-one                  (8) 3,7,11,15tetramethyl-2,6,10,14-hexadecatetraenoic acid                    (9) 6,10,14,18tetramethyl-5,9,13,17-nonadecatetraene-2-one               

As seen from the data in Table 1, the polyprenyl compounds of theformula (I) are effective against papillomata.

Toxicity Tests (1) Test procedure

The test compound was administered repeatedly to a group of 6 mice (ICRstrain, female) for 14 days in the dosage of 200 mg./kg./day. In thecourse of the administration procedures, increase or decrease of theweight of the mouse, occurrence of death, etc. were observed.

(2) Test compound

The compounds set forth in the above Table 1 were employed.

(3) Test results

No death was observed. Decrease of the weight was not observed, and alittle increase of the weight was observed. No symptoms indicating sideeffects, such as falling-out of hair, cyanosis, etc., were observed.

The decrease of the weight and the falling-out of hair are known asindicating the hypervitaminosis of Vitamin A. Accordingly, the resultsare considered to indicate that the polyprenyl compounds of the formula(I) do not cause the hypervitaminosis of Vitamin A.

In view of the pharmacological test results and the toxicity testresults as described hereinbefore, the polyprenyl compounds of theformula (I) are judged to be of high safety and to be of value asanti-cancer agents for treatment of cancer and precancerous conditions.

It is well known that mouse papillomata as mentioned above are useful asa model for proliferous keratinization. Accordingly it is understoodfrom the above shown data that the compound according to the inventionis effective also on skin diseases with keratinization.

For the treatment of skin diseases with keratinization and allergic orinflammatory skin diseases, the polyprenyl compound of the formula (I)can be administered orally in the form of a powder, granules, pellets,hard capsules, etc., or parenterally in the form of ointment,suppository, injection solution, etc. The dosage is generally set in therange of 40 mg. to 4 g./day for an adult human being. If the polyprenylcompound of the formula (I) is applied in the form of an externalpreparation, the dosage can be varied depending on the largeness of areaof the affected part. The above-mentioned preparations can be preparedfrom the polyprenyl compound of the invention and generally employablecarriers for the medical use by utilizing the conventional methods.

The following examples will illustrate processes for preparing thepolyprenyl compounds of the formula (I) and the preparations comprisingthe polyprenyl compounds, but these examples are not given to restrictthe present invention.

PREPARATION EXAMPLE 1 Ethyl3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoate

To a suspension of 2.5 g. of 55% sodium hydride (in oil) in 30 ml. ofn-hexane was added 13.6 g. of triethyl phosphonoacetate. The mixture wasthen heated under reflux, and 10 g. of6,10,14-trimethyl-3,5,13-pentadecatriene-2-one was added dropwise to themixture under stirring. After 30 minutes, the reaction liquid was pouredinto 100 ml. of ice-water, and then 200 ml. of n-hexane was added forextraction. The n-hexane phase was separated, washed with two 50 ml.portions of a mixture of methanol and water (2:1), and concentrated. Theso obtained concentrate was purified by the silica gel columnchromatography to give 9.0 g. of the desired product as an oil.

    ______________________________________                                        Analysis for C.sub.22 H.sub.36 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     79.46  10.92                                               Found (%)          79.74  11.04                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 0.87 (3H, d, J=6 Hz), 1.28 (3H, t, J=7 Hz),1.0-1.6 (7H), 1.61 (3H, s), 1.69 (3H, s), 1.85 (3H, s), 1.9-2.4 (4H),23.4 (3H, d, J=1 Hz), 4.17 (2H, q, J=7 Hz), 5.10 (1H, t, J=7 Hz), 5.75(1H, bs), 5.95 (1H, d, J=11 Hz), 6.16 (1H, d, J=15 Hz), 6.86 (1H, dd,J=15 Hz, 11 Hz).

Mass spectrum (m/e): 332 (M⁺).

PREPARATION EXAMPLE 2 3,7,11,15-Tetramethyl-2,4,6,14-hexadecatetraenoicacid

To 8.0 g. of the ethyl3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoate obtained in theprevious Preparation Example 1 was added to a solution of 3.2 g. ofpotassium hydroxide in 20 ml. of isopropyl alcohol, and the mixture wasstirred at 50° C. for 1 hour. The reaction liquid was then poured intoice-water, made acidic by addition of hydrochloric acid, and extractedwith 50 ml. of diethyl ether. The ether phase was washed with water,dried over magnesium sulfate, and concentrated to give 7. g. of an oil.The oil was dissolved in 40 ml. of n-hexane and crystallized at -20° C.to give 3.1 g. of the desired product as white crystals.

M.p.: 60°-62° C.

    ______________________________________                                        Analysis for C.sub.20 H.sub.32 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     78.89  10.59                                               Found (%)          78.77  10.63                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 0.87 (3H, d, J=6 Hz), 1.0-1.6 (7H), 1.60 (3H,s), 1.69 (3H, s), 1.85 (3H, s) 1.9-2.3 (4H), 2.34 (3H, d, J=1 Hz), 5.10(1H, t, J=7 Hz), 5.77 (1H, bs), 5.97 (1H, d, J=11 Hz), 6.20 (1H, d, J=15Hz), 6.91 (1H, dd, J=15 Hz, 11 Hz), 9.6 (1H, b).

Mass spectrum (m/e): 304 (M⁺).

PREPARATION EXAMPLE 33,7,11,15-Tetramethyl-2,4,6,8,10,14-hexadecahexaenoic acid

To a suspension of 30.3 g. of sodium ethoxide in 300 ml. oftetrahydrofuran was added 118 g. of diethyl3-ethoxycarbonyl-2-methyl-2-propenylphosphonate. To the mixture wasadded 67 g. of 3,7,11-trimethyl-2,4,6,10-dodecatetraene-1-al understirring, chilling with ice and shielding from the light. After 1 hour,the reaction liquid was poured into 1 liter of water, and 1 liter ofn-hexane was added for extraction. The n-hexane phase was separated,washed with two 100 ml. portions of a mixture of methanol and water(2:1), and concentrated to give 99 g. of a concentrate. To a refluxingsolution of 8.2 g. of potassium hydroxide and 80 ml. of isopropylalcohol was added 21 g. of the concentrate under shielding from thelight. After 15 minutes, the reaction liquid was poured into 300 ml. ofice-water, made acidic by addition of hydrochloric acid, and extractedwith 300 ml. of diethyl ether. The extract was washed with three 100 ml.portions of water, dried over magnesium sulfate, and evaporated toremove the solvent. The residue was dissolved in 200 ml. of n-hexane andchilled to -20° C. to crystallize it. There was obtained 9.8 g. of thedesired product as pale yellow crystals.

    ______________________________________                                        Analysis for C.sub.20 H.sub.28 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     79.95  9.39                                                Found (%)          80.22  9.47                                                ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.63 (3H, s), 1.69 (3H, s), 1.84 (3H, s), 1.99(3H, s), 2.0-2.3 (4H), 2.36 (3H, s), 5.15 (1H, m), 5.6-7.2 (7H, m), 1.04(1H, b).

Mass spectrum (m/e): 300 (M⁺).

PREPARATION EXAMPLE 43,7,11,15,19-Pentamethyl-2,4,6,10,14,18-eicosahexaenoic acid

In 100 ml. of tetrahydrofuran was dissolved 12 g. of1-p-tolylsulfonyl-3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraene, andthe solution was chilled to -50° C. To the solution was added dropwise18.5 ml. of 15% n-butyllithium-n-hexane solution under stirring and in astream of nitrogen, maintaining the temperature of the solution at -50°C. Then, 300 ml. of tetrahydrofuan solution containing 5.7 g. of ethyl4-bromo-3-methyl-2-butenate was added dropwise to the so producedsolution. After 30 minutes, 100 ml. of 10% aqueous ammonium chloridesolution was added, and then the mixture was allowed to stand to reachroom temperature. The mixture was subsequently extracted with two 200ml. portions of n-hexane. The n-hexane phase was washed with three 100ml. portions of water, dried over magnesium sulfate, and evaporated toremove the solvent. There was obtained 14 g. of ethyl3,7,11,15,19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18-eicosapentaenoate.

To 4.1 g. of potassium hydroxide in 50 ml. of isopropyl alcohol wasadded 12 g. of the above-obtained ethyl3,7,11,15,19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18-eicosapentaenoate,and the mixture was stirred at 50° C. for 3 hours. The reaction liquidwas poured into ice-water, made acidic by addition of hydrochloric acid,and extracted with 100 ml. of diethyl ether. The extract was washed withwater, dried over magnesium sulfate and evaporated to remove thesolvent. Tere was obtained 8.5 g. of an oil. The so obtained oil wasdissolved in 40 ml. of n-hexane and chilled to -20° C. to crystallizeit. There was obtained 2.3 g. of the desired product as white crystals.

M.p.: 45.5°-46.5° C.

    ______________________________________                                        Analysis for C.sub.25 H.sub.38 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     81.03  10.34                                               Found (%)          80.89  10.52                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.60 (9H, s), 1.68 (3H, s), 1.86 (3H, s),1.9-2.3 (12H), 2.33 (3H, s), 5.09 (3H, b), 5.76 (1H, bs), 5.96 (1H, d,J=10 Hz), 6.18 (1H, d, J=15 Hz), 6.89 (1H, dd, J=15 Hz, 10 Hz), 10.2(1H, b).

Mass spectrum (m/e): 370 (M⁺).

PREPARATION EXAMPLE 5 Ethyl3,7,11,15-tetramethyl-2,4,6-hexadecatrienoate

The procedures described in Preparation Example 1 were repeated using6,10,14-trimethyl-3,5-pentadecadiene-2-one to obtain the desired productas an oil.

    ______________________________________                                        Analysis for C.sub.22 H.sub.38 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     78.98  11.45                                               Found (%)          79.16  11.56                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 0.87 (9H, d, J=7 Hz), 1.27 (3H, t, J=7 Hz),0.9-1.6 (12H), 1.84 (3H, s), 2.08 (2H, t, J=7 Hz), 2.34 (3H, s), 4.16(2H, q, J=7 Hz), 5.74 (1H, bs), 5.95 (1H, d, J=11 Hz), 6.16 (1H, d, J=15Hz), 6.85 (1H, dd, J=15 Hz, 11 Hz).

Mass spectrum (m/e): 334 (M⁺).

PREPARATION EXAMPLE 6 3,7,11,15-Tetramethyl-2,4,6-hexadecatrienoic acid

The procedures described in Preparation Example 2 were repeated usingthe ethyl 3,7,11,15-tetramethyl-2,4,6-hexadecatrienoate obtained inPreparation Example 5 to carry out the hydrolysis. There was obtainedthe desired product as white crystals.

M.p.: 84.5°-85.5° C.

    ______________________________________                                        Analysis for C.sub.20 H.sub.34 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     78.38  11.18                                               Found (%)          78.35  11.21                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 0.87 (9H, d, J=7 Hz), 0.9-1.6 (12H), 1.84 (3H,s), 2.09 (2H, t, J=7 Hz), 2.35 (3H, s), 5.76 (1H, bs), 5.96 (1H, d, J=11Hz), 6.19 (1H, d, J=15 Hz), 6.90 (1H, dd, J=15 Hz, 11 Hz), 11.5 (1H, b)

Mass spectrum (m/e): 306 (M⁺)

PREPARATION EXAMPLE 7 Ethyl3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate

To a suspension of 5.0 g. of 55% sodium hydride (in oil) in 60 ml. ofn-hexane was added 28.6 g. of triethyl phosphonoacetate. The mixture wasthen heated under reflux, and 20 g. of6,10,14-trimethyl-3,5,9,13-pentadecatetraene-2-one was added dropwise tothe mixture under stirring. After 30 minutes, the reaction liquid waspoured into 200 ml. of ice-water, and then 500 ml. of n-hexane was addedfor extraction. The n-hexane phase was separated, washed with two 100ml. portions of a mixture of methanol and water (2:1), and concentrated.The so obtained concentrate was purified by silica gel columnchromatography to give 18 g. of the desired product as an oil.

    ______________________________________                                        Analysis for C.sub.22 H.sub.34 O.sub.2                                                         C    H                                                       ______________________________________                                        Calculated (%)     79.95  10.37                                               Found (%)          80.11  10.26                                               ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.28 (3H, t, J=7 Hz), 1.60 (6H, s), 1.68 (3H,s), 1.85 (3H, s), 1.9-2.3 (8H), 2.33 (3H, d, J=1 Hz), 4.16 (2H, q, J=7Hz), 5.09 (2H, b), 5.73 (1H, bs), 5.96 (1H, d, J=11 Hz), 6.16 (1H, d,J=15 Hz), 6.85 (1H, dd, J=15 Hz, 11 Hz).

Mass spectrum (m/e): 330 (M⁺).

PREPARATION EXAMPLE 83,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoamide

To 3.9 g. of potassium hydroxide in 30 ml. of isopropyl alcohol wasadded 10 g. of the ethyl3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate obtained inPreparation Example 7, and the mixture was stirred at 50° C. for 1 hour.The reaction liquid was poured into ice-water, made acidic by additionof hydrochloric acid, and extracted with 100 ml. of diethyl ether. Theether phase was washed with water, dried over magnesium sulfate andconcentrated to give 9.0 g. of an oil. The so obtained oil was dissolvedin 50 ml. of n-hexane and chilled to -20° C. to crystallize it. Therewas obtained 4.0 g. of3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid as pale yellowneedles.

In 20 ml. of diethyl ether was dissolved 3.0 g. of the above-obtained3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To thissolution was added 1 g. of triethylamine, and further added 1.1 g. ofethyl chlorocarbonate under stirring at room temperature. After 10minutes, gaseous ammonia was introduced into the solution. The reactionliquid was washed with three 10 ml. portions of water, dried overmagnesium sulfate, and evaporated to remove the solvent. The residue waspurified by alumina column chromatography and crystallized from amixture of acetone and n-hexane (1:2). There was obtained 1.7 g. of thedesired product as pale yellow crystals.

M.p.: 63°-65° C.

    ______________________________________                                        Analysis for C.sub.20 H.sub.31 NO                                                       C          H      N                                                 ______________________________________                                        Calculated (%)                                                                            79.67        10.37  4.65                                          Found (%)   79.48        10.59  4.73                                          ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.60 (6H, s), 1.68 (3H, s), 1.84 (3H, d, J=1Hz), 1.9-2.3 (8H), 2.33 (3H, d, J=1 Hz), 5.08 (2H, m), 5,70 (1H, bs),5.4-6.1 (2H, b), 5.95 (1H, d, J=11 Hz), 6.15 (1H, d, J=15 Hz), 6.82 (1H,dd, J=15 Hz, 11 Hz).

Mass spectrum (m/e): 301 (M⁺).

PREPARATION EXAMPLE 9N-(p-Hydroxyphenyl)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

In 30 ml. of tetrahydrofuran was dissolved 3 g. of3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To thissolution was added 1 g. of triethylamine, and further added 1.1 g. ofethyl chlorocarbonate under stirring at room temperature. After 10minutes, the reaction liquid was poured into 100 ml. of water, andextracted with 100 ml. of n-hexane. The extract was washed with 50 ml.of water and evaporated to remove the solvent. The residue was dissolvedin 30 ml. of tetrahydrofuran. To this solution was added 1.1 g. ofp-aminophenol, and the mixture was stirred at room temperature for 30minutes. To the reaction liquid was added 200 ml. of diethyl ether, andthe mixture was washed successively with two 50 ml. portions of dilutehydrochloric acid and two 50 ml. portions of water. The ether phase wasdried over magnesium sulfate and evaporated to remove the solvent. Theresidue was crystallized from ethanol to obtain 3.2 g. of the desiredproduct as pale yellow crystals.

M.p.: 163°-164° C.

    ______________________________________                                        Analysis for C.sub.26 H.sub.35 NO.sub.2                                                 C          H      N                                                 ______________________________________                                        Calculated (%)                                                                            79.34        8.96   3.56                                          Found (%)   79.61        8.78   3.62                                          ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.61 (6H, s), 1.68 (3H, s), 1.85 (3H, s),1.9-2.3 (8H), 2.38 (3H, s), 5.09 (2H, m), 5.76 (1H, bs), 5.96 (1H, d,J=11 Hz), 6.15 (1H, d, J=15 Hz), 6.42 (1H, b), 6.74 (2H, d, J=8 Hz),6.82 (1H, d, J=15 Hz, 11 Hz), 7.22 (1H, bs), 7.32 (2H, d, J=8 Hz)

Mass spectrum (m/e): 393 (M⁺)

PREPARATION EXAMPLE 10N-Ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and ethylaminewere reacted in the same manner as in Preparation Example 9 to obtainthe desired product as an oil.

    ______________________________________                                        Analysis for C.sub.22 H.sub.35 NO                                                       C          H      N                                                 ______________________________________                                        Calculated (%)                                                                            80.19        10.71  4.25                                          Found (%)   80.44        10.79  4.38                                          ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.15 (3H, t, J=7 Hz), 1.60 (6H, s), 1.67 (3H,s), 1.83 (3H, s), 1.9-2.3 (8H), 2.33 (3H, d, J=1 Hz), 3.27 (2H, qd, J=7Hz, 6 Hz), 5.10 (2H, m), 5.65 (1H, bs), 5.82 (1H, t, J=6 Hz), 5.94 (1H,d, J=11 Hz), 6.10 (1H, d, J=15 Hz), 6.77 (1H, dd, J=15 Hz, 11 Hz).

Mass spectrum (m/e): 329 (M⁺).

PREPARATION EXAMPLE 11N,N-Dimethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide

3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid anddimethylamine were reacted in the same manner as in Preparation Example9 to obtain the desired product as pale yellow crystals.

M.p.: 39°-39.5° C.

    ______________________________________                                        Analysis for C.sub.22 H.sub.35 NO                                                       C          H      N                                                 ______________________________________                                        Calculated (%)                                                                            80.19        10.71  4.25                                          Found (%)   80.26        10.83  4.32                                          ______________________________________                                    

NMR spectrum (δ, CDCl₃): 1.60 (6H, s), 1.68 (3H, s), 1.76 (3H, s), 2.09(3H, d, J=1 Hz), 1.9-2.3 (8H), 3.00 (3H, s), 3.01 (3H, s), 5.10 (2H, m),5.93 (1H, bs), 5.94 (1H, d, J=10 Hz), 6.18 (1H, d, J=15 Hz), 6.68 (1H,dd, J=15 Hz, 10 Hz).

Mass spectrum (m/e): 329 (M⁺).

EXAMPLE 1

    ______________________________________                                        Tablet Preparation                                                            ______________________________________                                        N-Ethyl-3,7,11,15-tetramethyl-                                                                          50    g.                                            2,4,6,10,14-hexadecapentaenoamide                                             Silicic anhydride         30    g.                                            Crystalline cellulose     50    g.                                            Corn starch               36    g.                                            Hydroxypropylcellulose    10    g.                                            Magnesium stearate        4     g.                                            ______________________________________                                    

The above-described composition was processed in the conventional mannerto produce tablets (180 mg. per one tablet).

We claim:
 1. A method for treating skin diseases with keratinization andallergic or inflammatory skin diseases which comprises administering apolyprenyl compound having the formula (I): ##STR24## in which each of nand m is 0, 1 or 2, n+m is 0, 1 or 2, A is ##STR25## and B is ##STR26##wherein R is hydroxy, lower alkoxy, or ##STR27## in which each of R₁ andR₂ is hydrogen, lower alkyl or aryl; with the proviso that R is loweralkoxy or ##STR28## when n is 1, m is 0, A is ##STR29## and B is##STR30## to a patient orally or parenterally in the dosage ranging from40 mg to 4 g/day for an adult human being.
 2. A method as claimed inclaim 1 in which said polyprenyl compound is3,7,11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoic acid.
 3. Amethod as claimed in claim 1 in which said polyprenyl compound is3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoic acid.
 4. A method asclaimed in claim 1 in which said polyprenyl compound is ethyl3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoate.
 5. A method asclaimed in claim 1 in which said polyprenyl compound is3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecahexaenoic acid.
 6. A methodas claimed in claim 1 in which said polyprenyl compound isN-ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaeneamide.
 7. Amethod as claimed in claim 1 in which said polyprenyl compound is ethyl3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoate.
 8. A method asclaimed in claim 1 in which said polyprenyl compound is6,10,14,18-tetramethyl-3,5,9,13,17-nonadecapentaene-2-one.
 9. A methodas claimed in claim 1 in which said polyprenyl compound is3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid.
 10. A method asclaimed in claim 1 in which said polyprenyl compound is6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraene-2-one.